Extracellular matrix (ECM) structures for tissue regeneration

ABSTRACT

An extracellular matrix (ECM) structure for tissue regeneration, the ECM structure having a a sheet member comprising small intestine submucosa (SIS), the SIS sheet member being folded and laminated proximate the sheet member edge, wherein a folded laminated ECM structure having a cavity therein is formed, the ECM structure further including an ECM composition that is disposed in the ECM structure cavity, the ECM composition including liver basement membrane, urinary bladder submucosa, a mesenchymal stem cell and a growth factor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/306,368, filed on Jun. 17, 2014, which is a continuation of U.S.application Ser. No. 13/033,102, filed on Feb. 23, 2011, now U.S. Pat.No. 8,758,448, which is a continuation of U.S. application Ser. No.12/394,914, filed on Feb. 27, 2009, now abandoned, which is acontinuation of U.S. application Ser. No. 11/747,004, filed on May 10,2007, now abandoned, which applications are hereby incorporated hereinby reference in their entireties.

FIELD OF THE INVENTION

The invention relates to articles and compositions having two or moreforms of extracellular matrix.

BACKGROUND OF THE INVENTION

Tissue regeneration has been accomplished by using extracellular matrixmaterial derived from mammalian tissues. Some of these mammalian tissuesthat have been described in patent literature include small intestinesubmucosa (SIS), liver basement membrane (LBM), urinary bladdersubmucosa (UBS) and stomach submucosa (SS). See U.S. Pat. Nos.5,554,389, 4,902,508, and 5,281,422. Enamel matrices, which are theextracellular matrix around forming teeth, are described in U.S. Pat.No. 7,033,611. Extracellular matrices from these tissues have beenisolated and dried to become solid materials (sheets and particulates).Particulate forms can be rehydrated in a suitable buffer to becomefluidized or emulsive forms. Presently, these extracellular matrixcompositions are used for tissue grafting, wound healing, and tissueregenerative purposes.

It would be advantageous to the field of tissue engineering to inventarticles and compositions for effecting improved tissue regeneration.

SUMMARY OF THE INVENTION

The present invention is directed to extracellular matrix (ECM)structures as an implantable medical product for inducing tissueregeneration. The present invention is further directed to ECMstructures having cavities therein that are configured to encase ECMcompositions therein.

In a preferred embodiment of the invention, the ECM structure comprisesa sheet member comprising small intestine submucosa (SIS), the SIS sheetmember being folded and laminated proximate the sheet member edge as abioremodelable pouch structure, wherein a folded laminated ECM structurehaving an internal cavity therein is formed, the ECM structure furtherincluding an ECM composition that is disposed in the ECM structurecavity, the ECM composition including liver basement membrane, urinarybladder submucosa, a cell and a growth factor.

In one embodiment, the cell comprises a mesenchymal stem cell.

In one embodiment, the cell comprises a pluripotent cell.

In one embodiment of the invention, the growth factor comprises afibroblast growth factor-2 (FGF-2).

In one embodiment of the invention, the growth factor comprises avascular epithelial growth factor (VEGF).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a front plan view of two sheets of extracellular matrix (ECM)that can be employed to form one embodiment of a multi-sheet ECMstructure, in accordance with the invention;

FIG. 1B is a front plan view of a laminated multi-sheet ECM structureformed from the ECM sheets shown in FIG. 1A, in accordance with theinvention;

FIG. 1C is a perspective view of the multi-sheet ECM structure shown inFIG. 1B, in accordance with the invention;

FIG. 1D is a perspective view of a round laminated multi-sheet ECMstructure, in accordance with the invention;

FIG. 1E is a perspective view of a triangular shaped laminatedmulti-sheet ECM structure, in accordance with the invention;

FIGS. 2A and 2B are front sectional views of a laminated multi-sheet ECMstructure, i.e. a bioremodelable pouch structure, having an ECMcomposition disposed in the ECM article internal cavity, in accordancewith an embodiment of the invention;

FIGS. 2C and 2D are perspective views of ECM sheets with an ECMcomposition disposed therebetween, in accordance with the invention; and

FIGS. 3A-3C are perspective views of a folded ECM sheet with an ECMcomposition disposed therebetween, i.e., a bioremodelable pouchstructure, in accordance with an embodiment of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention is an article made of extracellular matrix as animplantable medical product for placing in a mammal at a site in need oftissue regeneration or wound healing to cause tissue regeneration andwound healing. These articles are made from extracellular matrices thatare derived from one or more than one tissue source in one or more donormammals.

In some embodiments, the article comprises a laminate of two or moresheets of extracellular matrix, i.e., the sheets are made of a pluralityof layers of extracellular matrix material. Accordingly, two componentsof such an article are first and second sheets of extracellular matrix,that are laminated together to form a laminate of extracellular matrixsheets. The two sheets in this example can be from the same source ofextracellular matrix, i.e. both or all from SIS from a pig. The sheetscan also be from different tissue sources of extracellular matrix, forexample the first sheet is SIS, and the second sheet is SS. Both the SISand SS can be from the same species of mammal (e.g. pig) or each from adifferent species of mammal (SIS from pig, and SS from cow). If thereare 3 sheets in the laminate article all 3 can be SIS, or the firstsheet can be SIS, the second SS, and the third sheet can be SIS, forexample. These three sheets can be from the same species of mammal, i.e.a pig, or different mammalian species, i.e. the SIS sheets can be from apig and the SS sheet can be from a cow.

Advantages are to be derived from using sheets of extracellular matrixfrom different mammalian tissues, where, for example, each tissue sourceprovides certain attributes. For example, SIS provides tensile strengthand the kind of support to newly forming tissue that one would attributeto small intestine submucosa. Adding a sheet from a different tissue,for example one without the tensile strength, but with otherregenerative attributes, for example liver basement membrane (LBM), canlend to the article that is a laminate of sheets, an advantageousquality, particularly when two such sheets are laminate together. Asandwich configuration of such sheets can be formed, for example withtwo outer sheets having relatively substantial tensile strength and aninner sheet of something less strong having other attributes, such asLBM. A SIS-LBM-SIS sheet sandwich may provide the appropriate matrix fortissue regeneration for certain tissues in the body having certainrequirements both for strength and regenerative potential.

In some embodiments, the structure comprises two sheets of extracellularmatrix that are configured to encase a composition. In a preferredembodiment, two extracellular matrix sheets each having edges that arepartially or completely joined together. In another preferredembodiment, the edges are partially joined so that the material can oozeout from the internal cavity. According to the invention, thecomposition can be any dispersible composition comprising a cell orcells that can rest upon a sheet of extracellular matrix and be covered(and encased by) another sheet. The composition can comprise a cell orcells, such as for example a plurality of stem cells that can aide andpromulgate tissue regeneration from the article after placement in thepatient. So then, for example the sheets can be SIS and the compositioncan comprise LBM, or the sheets can be SIS and the gel composition canalso be SIS.

For any of these articles, the sheets can be laminated to each other atthe edges around an amount of composition (comprising for example cellsand other components) that then becomes encased in the two sheets uponlamination of the outer sheets to each other, i.e., the pouch containsin the internal cavity a biologically active agent, gelatinoussemi-solid, or powder material. The lamination of the two outer sheetstogether can be partial or complete, i.e. the edges are partially orcompletely joined together, so that the composition can be entirelycontained within the two sheets, or can be permitted to ooze out frombetween the sheets upon placement in the subject receiving treatment. Ina preferred embodiment, the edges are completely laminated or sealedtogether. The composition comprising the cells can also be a compositionthat supports the cells and allows them to survive and differentiate inthat environment.

In another embodiment, the sheets can encase one or more cells. The cellor cells can be stem cells. The sheet sandwich can act as support forthe growth and development of the cells once placed in the body. Thecell or cells can advantageously work in the article to regeneratetissue, or heal damaged tissue in conjunction with the extracellularmatrix sheets. The cell or cells can be part of a composition comprisingsuch cells, such as cell media or other material that will help promotethe cell survival and differentiation.

The cell in the composition can be any cell, such as, for example ahuman embryonic stem cell, a fetal cardiomyocyte, a myofibroblast, amesenchymal stem cell, an autotransplanted expanded cardiomyocyte, anadipocyte, a totipotent cell, a pluripotent cell, a blood stem cell, amyoblast, an adult stem cell, a bone marrow cell, a mesenchymal cell, anembryonic stem cell, a parenchymal cell, an epithelial cell, anendothelial cell, a mesothelial cell, a fibroblast, a myofibroblast, anosteoblast, a chondrocyte, an exogenous cell, an endogenous cell, a stemcell, a hematopoetic stem cell, a pluripotent stem cell, a bonemarrow-derived progenitor cell, a progenitor cell, a myocardial cell, askeletal cell, a fetal cell, an embryonic cell, an undifferentiatedcell, a multi-potent progenitor cell, a unipotent progenitor cell, amonocyte, a cardiomyocyte, a cardiac myoblast, a skeletal myoblast, amacrophage, a capillary endothelial cell, a xenogenic cell, an allogeniccell, an adult stem cell, and a post-natal stem cell. This list is notintended to be exhaustive.

The composition comprising a cell or cells can comprise any materialsupportive of the purposes of the article and cell culture, cellsurvival and differentiation. Thus, for example, the composition cancomprise extracellular matrix that supports cells in culture and invivo. The composition can comprise any material supportive of thepurposes of the composition and the article in general, such as forexample tissue regeneration, wound healing, cell culturing and survival,cell differentiation, stem cell recruitment and the like.

Any composition to support the cells such as an extracellular matrixcomposition can comprise such forms of extracellular matrix as anemulsion, gel, liquid, paste or particulate placed in between the sheetsof matrix can be of mixed source of extracellular matrix, so that forexample the gel can be a 50:50 mixture of LBM and UBS. The compositioncan also be a mixture of LBM and UBS. Thus, the composition can be somemixture or ratio of extracellular matrix from one or more tissuesources.

Generally, for any of the articles of the invention, the components suchas sheets of extracellular matrix can be from the same mammalian tissuesource (e.g. SIS) or they can be from different tissue sources (e.g. aSIS sheet and an LBM emulsion). Mammalian tissue sources are in generalany tissue having an extracellular matrix that can be isolated from amammal and decellularized, i.e., acellular extracellular matrix. Thusfor example, most mammalian organs are tissue sources. The tissuesources can be for example any mammalian tissue, including but notlimited to the small intestine, large intestine, stomach, lung, liver,kidney, pancreas, placenta, heart, bladder, prostate, tissue surroundinggrowing tooth enamel, tissue surrounding growing bone, and any fetaltissue from any mammalian organ.

The forms of the extracellular matrices that make up the articles aregenerally sheets, although the sheets can be in any shape or sizenecessary for the site. Thus, for example the sheets can be square,rectangular, triangular, or circular. The sheets can be large or small,depending once again on the site that the article is to be placed.

Placement of the articles in the patients can be accomplished by anyreasonable means, including simply placing the article at the site ofdefect, or attaching the article in place, e.g. by glue or suture.

Extracellular matrix can be obtained from the tissues of mammals byprocesses such as described in U.S. Pat. Nos. 5,554,389, 4,902,508 and5,281,422. For example, the urinary bladder submucosa is anextracellular matrix that has the tunica mucosa (which includes thetransitional epithelial layer and the tunica propria), a submucosallayer, 3 layers of muscularis, and the adventitia (a loose connectivetissue layer). This general configuration is true also for smallintestine submucosa (SIS) and stomach submucosa (SS). Obtaining enamelmatrices is described in U.S. Pat. No. 7,033,611. Enamel matrix isextracellular matrix existing near forming teeth.

Other tissues such as the liver and pancreas have a basement membranethat does not demonstrate the kind of tensile strength of the tissuesdefined as submucosa. However, other useful properties may beopportunistically employed from the extracellular matrices of suchtissues as the liver, pancreas, placenta and lung tissues which haveeither basement membrane for extracellular matrix or interstitialmembrane (as with the lung). These softer matrices support cells such asthose in the organs from which the matrices are derived. Thus, certainbenefits are to be found in using the extracellular matrices of thesetissues, especially in combination with other such matrices like SIS andSS that may be stronger and which offer their particular advantages. Theextracellular matrices surrounding developing tooth enamel anddeveloping bone also have particular advantages over other matrices inthat they support the growth and differentiation of the hard tissues ofbone and enamel.

Matrices can be used in whole or in part, so that for example, anextracellular matrix can contain just the basement membrane (ortransitional epithelial layer) with the sub-adjacent tunica propria, thetunica submucosa, tunica muscularis, and tunica serosa. The matrixcomposition can contain any or all of these layers, and thus couldconceivably contain only the basement membrane portion, excluding thesubmucosa. However, generally, and especially since the submucosa isthought to contain and support the active growth factors and otherproteins necessary for in vivo tissue regeneration, the matrixcomposition from any given source will contain the active extracellularmatrix portions that support cell development and differentiation andtissue regeneration. Thus it is generally understood by persons of skillin the art that the extracellular matrix of any of the mammalian tissueconsists of several basically inseparable layers broadly termedextracellular matrix. Where layers can be separated these separatelayers can electively be included in the composition, depending onwhether they serve the purpose that is the goal of the article beingmade.

The bioremodelable pouch structure comprises an extracellular matrixstructure in sheet form, said extracellular matrix structure comprisingacellular extracellular matrix from a decellularized mammalian tissuesource. The sheets can come from one or more sources of mammalianextracellular matrix. Thus, for example, the composition can compriseextracellular matrix combinations from such sources as, for example butnot limited to, small intestine submucosa, liver basement membrane,stomach submucosa, urinary bladder submucosa, placental basementmembrane, pancreatic basement membrane, large intestine submucosa, lunginterstitial membrane, respiratory tract submucosa, heart extracellularmatrix, dermal matrix, and in general extracellular matrix from anymammalian fetal tissue. Generally a given sheet will be of one source ofextracellular matrix, but if the article has two sheets, one sheet canbe from one tissue source, and the second sheet can be from a second,different, tissue source.

The compositions of the invention can be made as follows: cells areselected for seeding and placing in between the sheets of extracellularmatrix. The cell media is selected and the cells cultured to viabilityand then placed in the article.

In making the laminates, the ends of the sheets can be sealed using anyreasonable means to do so, such as for example gluing or suturing thesheets to each other to form the article. In a preferred embodiment, thepouch structure has a rectangular configuration with one closed end andthe edges of both sides joined together. If the sheets are encasing acomposition comprising a cell or cells, the sheets are laminated at theoutside edges and will encase the cells or cell composition. If a singlesheet is folded over to encase a composition, lamination occurs on threesides of the sheet. If a rectangular, or other-shaped article isconstructed from two or more sheets in a laminate, lamination occurs atthe edges of the article to seal the composition inside, or to affix thesheets together.

For example, sheets can be laminated or layered with each other, so thata sheet of SIS can be placed with a sheet of SS, either with two sheetstogether SIS-SS or as a sandwich with three sheets, for exampleSIS-SS-SIS, i.e., the sheet includes two or three layers of SISmaterial. Also, a different sandwich configuration can be made with twosheets of SIS or SS, sandwiching a gelatinous semi-solid or a solidpowder (particulate) material form of the matrix. The sandwich can beclosed so that a composition can be placed securely between the twoouter sheets. A single sheet can alternatively be folded over to encasean amount of composition.

Turning now to the figures, FIG. 1 depicts the laminate sheets in arectangle shape, and circular and triangle shapes. FIG. 1A depicts afirst rectangular sheet 10, and second rectangular sheet 11, beforelamination. FIG. 1B depicts rectangular sheet 10 and rectangular sheet11 laminated together to form laminated article 12. FIG. 1C depictslaminated article 12, having sheets 10 and 11 laminated together in a3-dimensional perspective to form rectangular laminated article 12. FIG.1D depicts circular laminated article 13 having laminated circularsheets 14 and 16 laminated together, i.e., the pouch has a peripherythat is round. FIG. 1E depicts laminated article 15 having a triangularshape, formed by lamination of triangular sheets 17 and 18 beinglaminated together.

FIG. 2A depicts two sheets, a top sheet 20 and a bottom sheet 22,overlaying a composition 24 comprising cells. FIG. 2B depicts a crosssectional view of the top sheet 20 and bottom sheet 22 laminated atpoint 26 to encase composition 24 in a bioremodelable pouch structure.FIG. 2C depicts a 3-dimensional view of top sheet 20 and bottom sheet 22with composition 24 in between the two sheets, ready for lamination.FIG. 2D depicts a circular article having top sheet 30 and bottom sheet32 with composition 34 in between them, i.e., the pouch has a peripherythat is round, ready for lamination to close the edges and prepare thearticle for insertion into a mammalian patient.

FIG. 3A depicts single sheet 40 encasing composition 42. FIG. 3B depictssingle sheet 40 encasing composition 42 having laminated edge 44 in abioremodelable pouch structure. FIG. 3C depicts single sheet 40 havingcomposition 42 with laminate points 46 on 3 sides of the article in abioremodelable pouch structure.

The pouch structure comprises an internal cavity, wherein the pouchstructure is configured to contain a material in the internal cavity.The laminate article can encase a composition. The composition cancomprise a cell or a plurality of cells. The composition can comprise astem cell or a plurality of stem cells. The composition can be amaterial that supports the culturing of the cells. The composition cancomprise extracellular matrix in gel or emulsion form that supports cellgrowth and survival.

The composition that might be encased in one or two sheets ofextracellular matrix in addition to comprising a cell or cells mightfurther comprise an additional component. The additional component canbe any component that serves the composition and its purpose in themammalian body. Thus, the additional component can help to regeneratetissue, heal a wound, better cultivate cells in the composition, betterrecruit endogenous stem cells once in the body, manipulate the immuneenvironment in a beneficial way, therapeutically treat the localenvironment, or otherwise contribute to some aspect of the process forwhich the composition and article that includes the composition is beingused.

Thus, the additional component can be a protein or a drug.

The protein can be for example a growth factor, or any other type orprotein that might stimulate some part of the tissue regenerativeprocess. a collagen, a proteoglycan, a glycosaminoglycan (GAG) chain, aglycoprotein, a growth factor, a cytokine, a cell-surface associatedprotein, a cell adhesion molecule (CAM), an angiogenic growth factor, anendothelial ligand, a matrikine, a matrix metalloprotease, a cadherin,an immunoglobin, a fibril collagen, a non-fibrillar collagen, a basementmembrane collagen, a multiplexin, a small-leucine rich proteoglycan,decorin, biglycan, a fibromodulin, keratocan, lumican, epiphycan, aheparan sulfate proteoglycan, perlecan, agrin, testican, syndecan,glypican, serglycin, selectin, a lectican, aggrecan, versican, nuerocan,brevican, cytoplasmic domain-44 (CD-44), macrophage stimulating factor,amyloid precursor protein, heparin, chondroitin sulfate B (dermatansulfate), chondroitin sulfate A, heparan sulfate, hyaluronic acid,fibronectin (Fn), tenascin, elastin, fibrillin, laminin,nidogen/entactin, fibulin I, fibulin II, integrin, a transmembranemolecule, platelet derived growth factor (PDGF), epidermal growth factor(EGF), transforming growth factor alpha (TGF-alpha), transforming growthfactor beta (TGF-beta), fibroblast growth factor-2 (FGF-2) (also calledbasic fibroblast growth factor (bFGF)), thrombospondin, osteopontin,angiotensin converting enzyme (ACE), and vascular epithelial growthfactor (VEGF). This list is not intended to be exhaustive.

The additional component can also be a drug, such as an agent that hastherapeutic properties. The drug can be bioactive and play some role inthe process of tissue regeneration or act as an antibiotic, antiviral,or other active therapeutic agent serving a purpose in the compositionas a whole. The drug can be a small molecule, or any other agent havingtherapeutic properties.

The bioremodelable pouch structure of the present invention effectivelyimproves biological functions by promoting tissue regeneration,modulated healing of adjacent tissue or growth of new tissue whenimplanted in a body of a warm blooded mammal. The invention contemplatesusing the articles of the invention for contacting a defect in mammaliantissue. The defect can be a cut, disease, wound, burn, scar, necrosis,or other abnormality that would be beneficial to treat. Regeneratingtissue at the defect can be one response elicited from the step ofplacing the extracellular matrix composition in contact with the defect.If the defect is a wound in need of healing, wound healing may beanother response that occurs as a result of placing the extracellularmatrix at the wound site. In general any term that identifies that thetissue could benefit from a healing or tissue regeneration fits withinthe scope of the use for the composition. Thus regenerating tissue, orhealing a wound are two but the not the only phrases that can be used todescribe the effects achieved when the composition is placed in themammal at a site of defect or damage in tissue.

Therapeutically effective amount is a term meant to capture the ideathat you need to apply enough of the composition in sufficient strengthso that the composition can have a positive effect on the tissue that isbeing treated in the subject. The amount may therefore apply to anamount of cell or cells in the composition encased by the laminate. Thatthe amount is therapeutically effective is determined by thecomposition's ability to have an effect on the regenerative or woundhealing activity provided by the article (that encases the composition)as a whole at the site where the article (and composition) contacts thetissue. A therapeutically effective amount is determinable by routinetesting in patients with wounds or defects. In general a minimaltherapeutically effective amount would be considered sufficient cells(or sufficient amount of an additional component) in the composition toeffect the wound healing or tissue regeneration at the site of placementof the article that contains the cells or the additional component.

Regenerating tissue, as is accomplished by placing an article of theinvention in a mammal in need of tissue regeneration, is the ability tomake tissue regrow, an organ regrow itself, and for tissue to reform ornew tissue to form without scarring. Healing a wound is the ability ofthe tissue to heal preferably without scarring or with very minimalscarring. All references cited are incorporated in their entirety.Although the foregoing invention has been described in detail forpurposes of clarity of understanding, it will be obvious that certainmodifications may be practiced within the scope of the appended claims.

What is claimed is:
 1. An implantable medical product, comprising: abioremodelable pouch structure comprising an extracellular matrix (ECM)structure in sheet form, said ECM structure comprising acellular ECMfrom a decellularized mammalian tissue source, said decellularizedmammalian tissue source being small intestine submucosa, liver basementmembrane, stomach submucosa, urinary bladder submucosa, placentalbasement membrane, pancreatic basement membrane, large intestinesubmucosa, lung interstitial membrane, respiratory tract submucosa,heart extracellular matrix, or dermal matrix; said pouch structurecomprising an internal cavity having an opening, wherein the pouchstructure is configured to contain an additional component orcomposition in the internal cavity; wherein the ECM structure providestensile strength to support newly forming tissue and includes first andsecond ECM sheets or sheet portions, each ECM sheet or sheet portionhaving single or plural layers and edges, wherein only the edges of theECM sheets or sheet portions are joined together by laminating, suturingor gluing except for the edges that form the opening to provide theinternal cavity that is located between the sheets or sheet portions;wherein the composition provided in the internal cavity of the pouchstructure comprises an antibiotic or a drug or a biologically activeagent, wherein the pouch structure effectively improves biologicalfunctions by promoting tissue regeneration, modulated healing ofadjacent tissue or growth of new tissue when implanted in a body of awarm blooded mammal.
 2. The product of claim 1, wherein the edges arejoined together by suturing.
 3. The product of claim 1, wherein thepouch structure has a rectangular configuration with one closed end andonly the edges of both sides of the ECM sheet portions adjacent theclosed end are joined together.
 4. The product of claim 1, wherein thecomposition contained in the internal cavity comprises cells or aprotein as the biologically active agent.
 5. The product of claim 1,wherein the composition contained in the internal cavity is abiologically active agent.
 6. The product of claim 1, wherein thecomposition contained in the internal cavity is a gelatinous semi-solidor powder material.
 7. The product of claim 6, wherein the edges arepartially joined so that the composition can ooze out from the internalcavity.
 8. The product of claim 1, wherein the pouch has a peripherythat is round.
 9. The product of claim 1, wherein the pouch has aperiphery that is generally rectangular.
 10. The product of claim 1,wherein each ECM sheet includes 2 or 3 layers of SIS material.
 11. Theproduct of claim 1, wherein the edges are completely laminated or joinedtogether.
 12. The product of claim 1, wherein the pouch structure has arectangular configuration with one closed end and only the edges of bothsides adjacent the closed end are joined together, and with thecomposition contained in the internal cavity of the pouch structurecomprising an antibiotic or a drug or a biologically active agent. 13.The product of claim 1, wherein the pouch structure has a roundconfiguration and the composition contained in the internal cavitycomprises an antibiotic or a drug or a biologically active agent. 14.The product of claim 13, wherein the additional composition in theinternal cavity of the pouch structure is in the form of a gelatinoussemi-solid or powder material, wherein the edges are partially joined sothat the material can ooze out from the internal cavity.
 15. Animplantable medical product, comprising: a bioremodelable pouchstructure comprising an extracellular matrix (ECM) structure in sheetform, said ECM structure comprising acellular ECM from a decellularizedmammalian tissue source, said decellularized mammalian tissue sourcebeing small intestine submucosa, liver basement membrane, stomachsubmucosa, urinary bladder submucosa, placental basement membrane,pancreatic basement membrane, large intestine submucosa, lunginterstitial membrane, respiratory tract submucosa, heart extracellularmatrix, or dermal matrix; said pouch structure comprising an internalcavity and an opening, wherein the pouch structure is configured toreceive and contain an additional component or composition in theinternal cavity; wherein the ECM structure provides tensile strength tosupport newly forming tissue and includes first and second ECM sheets orsheet portions, each ECM sheet or sheet portion having single or plurallayers and edges, wherein only the edges of the ECM sheets or sheetportions are joined together by laminating, suturing or gluing exceptfor the edges that form the opening to provide the internal cavity thatis located between the sheets or sheet portions; wherein the compositionprovided in the internal cavity of the pouch structure effectivelyimproves biological functions by promoting tissue regeneration,modulated healing of adjacent tissue or growth of new tissue whenimplanted in a body of a warm blooded mammal.
 16. The product of claim15, wherein the edges are joined together by suturing.
 17. The productof claim 15, wherein each ECM sheet is made of 2 or 3 layers of ECMmaterial and the pouch structure has a periphery that is round.
 18. Theproduct of claim 15, wherein each ECM sheet is made of 2 or 3 layers ofECM material and the pouch structure is generally rectangular.